Introduction: Sickle cell disease, the most common genetic disorder in France, was identified as a priority in the 2004 Public Health Act, with goals to reduce mortality and improve care and quality of life for those affected. Since 1980, alongside an increase in the age at death and a reduction in mortality among the youngest patients, there has been a steady rise in the annual number of deaths. As part of surveillance efforts, an analysis of trends in sickle cell disease-related mortality was conducted. Methods: This study analyzed death certificates for sickle cell disease-related deaths recorded between 1979 and 2010, using the specific codes for sickle cell disease from versions 9 and 10 of the International Classification of Diseases (ICD) for both primary and associated causes. Results: Over the 1979–2010 period, 953 deaths related to sickle cell disease were recorded in France. A decline in the median age at death was observed both in metropolitan France (from 21.5 years to 35.1 years between 1979–1994 and 1995–2010) and in the overseas departments (DOM) (from 27.0 years to 38.7 years between 1979–1994 and 1995–2010). All-age mortality rates increased over the period (from 0.30 per 100,000 in 1991–1995 to 0.35 per 100,000 in 2006–2010) in metropolitan France and remained stable in the DOM, following a period of decline between 1996 and 2000. Rates decreased significantly among children under 5 years of age, falling from 1.68/106 to 0.89/106 between 1991–1995 and 2006–2010. Sickle cell disease is the primary cause of death in more than half of all cases. For the remaining deaths, the causes correspond to the most common complications and comorbidities of sickle cell disease. Finally, the median age at death varies depending on the underlying cause. It is lower when the underlying cause is an infectious disease compared to other comorbidities. Conclusion: These results suggest that early screening combined with improved disease management during childhood has had a favorable impact on pediatric mortality related to sickle cell disease and on age at death.